The enzyme steroid sulfatase (E.C. 3.1.6.2., STS) catalyses the hydrolysis of estrone sulfate to estrone and of DHEA sulfate to DHEA (Dibbelt L, Biol. Chem., Hoppe-Seyler, 1991, 372, 173-185 and Stein C, J. Biol. Chem., 1989, 264, 13865-13872).
The steroid sulfatase pathway has been the focus of recent interest in the context of breast cancer, with regard to the local intra-tissue formation of estrogens from the abundant circulating pool of estrone sulfate (E1S) (Pasqualini J R, J. Steroid Biochem. Mol. Biol., 1999, 69, 287-292 and Purohit A, Mol. Cell. Endocrinol., 2001, 171, 129-135).
Inhibition of this enzyme would prevent E1S to yield free estrone (E1), which in turn can be transformed into estradiol (E2) by enzymatic reduction. In addition to the estrone sulfatase pathway, it is now believed that another potent estrogen, androstenediol (adiol) obtained from DHEA after hydrolysis of DHEA-S, could be another important route, in the support of growth and development of hormone dependent breast tumors.
The formation of estrogens in humans is schematically represented in FIG. 1.
In patients with hormone-dependent cancers, aromatase inhibitors are currently used to prevent estrogen synthesis. However, clinical trials showed a relative lack of efficacy for patients with estrogen receptors positive tumors (Castiglione-Gertsch M, Eur. J. Cancer, 1996, 32A, 393-395 and Jonat W, Eur. J. Cancer, 1996, 32A, 404-412). As an explanation, steroid sulfatase pathway could be another important route for estrogen formation in breast tumors.
EMATE (Ahmed S, Curr. Med. Chem., 2002, 9, 2, 263-273), estrone-3-sulfamate, is the historical standard steroid sulfatase inhibitor but with the major drawback of being estrogenic because of its mechanism of inhibition: the sulfamate moiety is cleaved during the process of enzyme inactivation, which releases E1, not from E1S but from EMATE itself (Ahmed S, J. Steroid Biochem. Mol. Biol., 2002, 80, 429-440).

Other non steroid sulfamate compounds which release derivatives without estrogenic properties are presented as acceptable drug candidates, in particular 6,6,7-COUMATE, a standard non-estrogenic sulfatase inhibitor from the literature (Purohit A, Cancer Res., 2000, 60, 3394-3396).
Accordingly, there is a need for steroid sulfatase inhibitors with the view of treating in particular estrogen-dependent diseases.